Evolution has favored the production of fibrinolases,metallo proteinases, and disintegrins in viper venoms to help snakes capture and digest their prey; however, when humans are envenomated this creates medical emergencies. These same molecules can be redesigned as molecules that stop the metastasis of tumors. Cell-to-cell interaction and cell-to-extracellular matrix adhesion are two important concepts that have lead to a better understanding of tumor biology. Disintegrins found in snake venoms bind to integdns on the surface of cells and alter the cell to cell and cell to matrix interaction; thereby, interfering with the internal and external functions of cells. These disintegrins are competitive inhibitors of ligands and have the potential of being used in medicine. A few disintegrins have been found in venoms that inhibit angiogenesis and metastasis. Snake venoms are rich, stable sources of disintegrins, metalloproteases, and fibrinolytic enzymes. The Natural Toxins Research Center (NTRC) at Texas A&M University-Kingsville (TAMUK) has developed a serpentarium that presently houses over 320 snakes composed of 14 species and 24 subspecies. The tong-term objective of the proposed research is to clone disintegrins found in snake venoms that inhibit the metastasis of tumors. The specific aims are to screen snake venom for disintegrins with various binding assays. It is our hypothesis that there are many undiscovered disintegrins in snake venom that can prevent metastasis of tumors. This information is critical for designing drugs. All snake venoms will be obtained from the NTRC at TAMUK and fractionated by size exclusion, ion exchange, and reversed phase HPLC. The venom and venom fractions will be initially screened with a sonoclot analyzer and other integrin binding assays. The low molecular weight venom fractions will be tested for blocking the adhesion of human breast cancer cells (MDAMB-425) to extracellular matrix (ECM) proteins such as fibronectin and vitronectin. Those fractions that bind to integrins will be further purified and tested for efficiency of preventing metastasis in animal models. Fractions that have positive binding activity will be tested for inhibition of experimental lung metastasis in C57BL/6 mice when injected IV with B16F10 murine melanoma cells. Those disintegrins that show the greatest promise will be cloned and retested by binding assays and in animal models for the prevention of metastasis, it is our hypothesis that snake venoms are excellent stable sources of disintegrins and have unique ways of preventing metastasis of tumors.